(3S,4S)-4-((R)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone of formula I is known for its usefulness as an intermediate for the preparation of tetrahydrolipstatin (orlistat) (U.S. Pat. Nos. 5,245,056 and 5,399,720, and Mark A. Schwindt. et. Al., Org. Process Research, December 2007, 524).
(2S,3S,5R)-3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one of formula IV has been used as the key starting material in the preparation of optically pure (3S,4S)-4-((R)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone of formula I or a derivative thereof having an easily deprotectable alkyl protecting group.

Such a preparative procedure, as described in U.S. Pat. No. 5,245,056, involves several steps as shown in scheme I:

That is, the compound of formula V is prepared by introducing a tetrahydropyranyl group to protect the hydroxy group of the compound of formula IV. Then, the compound of formula V is hydrolyzed to obtain the compound of formula VI, which is treated with a benzylation reagent to obtain the compound of formula VII. A deprotection reaction is conducted by treating the compound of formula VII with an acid, followed by an optical resolution of the resulting compound, to obtain optically pure (2S,3S,5R)-5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid of formula II. Finally, cyclization of the compound of formula II is conducted to obtain (3S,4S)-4-(R)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone of formula I.
However, the method has the problems of using complicated reaction steps that result in a low overall yield.
As for an alternative method, Korean Patent No. 191,365 discloses a procedure for preparing the compound of formula II starting from the compound of formula IV, as shown in scheme II:


The above procedure comprises: protecting the hydroxy group of the compound of formula IV by introducing a benzoyl group thereto, to obtain the compound of formula VIII, hydrolyzing the compound of formula VIII to obtain a compound of formula IX which is subject to benzylation reaction to obtain the compound of formula X, and the compound of formula X is hydrolyzed to obtain the compound of formula II. The above method also gives a low yield.
However, this method have problems in that the protection and the substituent deprotection of the hydroxy group of formula IV should be conducted; a hindrance is occurred and strong reaction conditions for benzylation are required, due to the structure of the compound of formula VIII which comprises a sterically large benzoyl group adjacent to the hydroxy group of 5′ position; and its overall yield is as low as 41.2%.
U.S. Pat. No. 5,399,720 discloses a method for preparing the benzylamine salt of (2S,3S,5R)-5-benzyloxy-2-hexyl-hydroxyhexadecanoic acid of formula IIa by way of using the compound of formula IV as a starting material, as shown in scheme III:


However, this method also suffers from the problems of a low overall yield (43%) due to the necessity of strong benzylation conditions and the necessity to conduct deprotection and hydrolyzation steps after the benzylation.
The present inventors have endeavored to solve the above problems of the methods of the prior art; and have found that the subject compound can be prepared in a high yield and high purity by hydrolyzing the compound of formula IV without protecting its hydroxyl group and subjecting the resulting compound to selective benzylation and cyclization.